Atherosclerosis is an inflammatory disease characterized by a large amount of hyperproliferation and poorly differentiated or undifferentiated smooth muscle cells in atherosclerotic plaque. Cancer cells differ from normal cells in many aspects, including hyperproliferation and loss of differentiation. So the research on tumor may shed light on the treatment of atherosclerosis. Given that Kruppel-like factor 4 (KLF4) has an important function in tumor development and progression, it may be associated with the formation and development of atherosclerosis. Recently, KLF4 expression has been documented in vascular endothelial cells. KLF4, which is normally not expressed in differentiated SMC in vivo, was rapidly up-regulated in response to vascular injury. In addition, KLF4 is a critical regulator in macrophage activation. Endothelial dysfunction, macrophage activation and VSMC phenotype switching are critical component elements in development of atherosclerosis. Herein we hypothesize that KLF4 is an important regulator in different phase of atherosclerosis and may be a novel target of prevention and cure of atherosclerosis. Further investigation is needed to approach the concrete signaling pathways about KLF4.